The present invention relates to certain benzimidazole derivatives and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. The invention also relates to the preparation of the benzimidazole derivatives and pharmaceutical formulations containing them.
Of the DNA viruses, those of the herpes group are the source of the most common viral illnesses in man. The group includes herpes simplex virus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6) and human herpes virus type 7 (HHV-7) and type 8 (HHV-8). HSV-1 and HSV-2 are some of the most common infectious agents of man. Most of these viruses are able to persist in the host""s neural cells; once infected, individuals are at risk of recurrent clinical manifestations of infection which can be both physically and psychologically distressing.
HSV infection is often characterized by extensive and debilitating lesions of the skin, mouth and/or genitals. Primary infections may be subclinical although tend to be more severe than infections in individuals previously exposed to the virus. Ocular infection by HSV can lead to keratitis or cataracts thereby endangering the host""s sight. Infection in the new-born, in immunocompromised patients or penetration of the infection into the central nervous system can prove fatal. VZV is a herpes virus which causes chickenpox and shingles. Chickenpox is the primary disease produced in a host without immunity, and in young children is usually a mild illness characterized by a vesicular rash and fever. Shingles or zoster is the recurrent form of the disease which occurs in adults who were previously infected with VZV. The clinical manifestations of shingles are characterized by neuralgia and a vesicular skin rash that is unilateral and dermatomal in distribution. Spread of inflammation may lead to paralysis or convulsions. Coma can occur if the meninges become affected. VZV is of serious concern in patients receiving immunosuppressive drugs for transplant purposes or for treatment of malignant neoplasia and is a serious complication of AIDS patients due to their impaired immune system.
In common with other herpes viruses, infection with CMV leads to a lifelong association of virus and host. Congenital HCMV disease is characterized by jaundice, hepatosplenomegaly, petechial rash and multiple organ dysfunction and is associated with long-term sequelae such as hearing loss and mental deficiency. Infection can result in retinitis leading to blindness or, in less severe forms, failure to thrive, and susceptibility to chest and ear infections. CMV infection in patients whose immune systems are immature or who are immunocompromised for example as a result of malignancy, treatment with immunosuppressive drugs following transplantation or infection with Human Immunodeficiency Virus, may give rise to retinitis, colitis, esophagistis, hepatitis, meningoencephalitis, pneumonitis, gastrointestinal disorders and neurological diseases. In addition, these CMV disease syndromes can affect patients who are not immunocompromised.
The main disease caused by EBV is acute or chronic infectious mononucleosis (glandular fever). Examples of other EBV or EBV associated diseases include lymphoproliferative disease which frequently occurs in persons with congenital or acquired cellular immune deficiency, X-linked lymphoproliferative disease which occurs namely in young boys, EBV-associated B-cell tumors, Hodgkin""s disease, nasopharyngeal carcinoma, Burkitt lymphoma, non-Hodgkin B-cell lymphoma, thymomas and oral hairy leukoplakia. EBV infections have also been found in association with a variety of epithelial-cell-derived tumors of the upper and lower respiratory tracts including the lung.
HHV-6 has been shown to be a causative agent of infantum subitum in children and of kidney rejection and interstitial pneumonia in kidney and bone marrow transplant patients, respectively, and may be associated with other diseases such as multiple sclerosis. There is also evidence of repression of stem cell counts in bone marrow transplant patients. HHV-7 is of undetermined disease etiology. HHV-8 has been implicated in cancer.
Hepatitis B virus (HBV) is a viral pathogen of world-wide major importance. The virus is etiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world""s liver cancer. Clinical effects of infection with HBV range from headache, fever, malaise, nausea, vomiting, anorexia and abdominal pains. Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease outlined above.
GB 682,960, GB 690,119 and GB 696,952 disclose benzimidazole glycosides useful as intermediates in the preparation of therapeutic substances. Mochalin et. al. (SU 443035; Zh. Org. Khim. 12(1), 58-63 (1976)) describe the synthesis of certain unsubstituted benzimidazote pyranosides. Gosselin et. al. (Antiviral Chem. Chemother. 5(4), 243-56, 1994) disclose certain 5,6,-dichlorobenzimidazole arabinopyranosyl compounds with antiviral activity. Townsend et. al. (Chemical Reviews, vol. 70 no. 3, 1970) discloses certain 1-glycosylbenzimidazoles. U.S. Pat. No. 5,585,394 discloses 1-benzenesulfonyl-1,3-dihyro-2H-benzimidazol-2-one derivatives which have affinity for the vasopressin and oxytocin receptors. EP 0 521 463 A2 describes certain cyclohexanol analogues for antiviral and anti-parasitic use.
It has now been discovered that certain 6-membered ring-containing benzimidazole derivatives are useful for the treatment or prophylaxis of viral infections. According to a first aspect of the present invention, there is provided compounds of formula (I) 
wherein:
R1 is halogen, hydroxy, azido, C1-8alkyl, C1-8alkoxy, C2-6alkenyl, C2-6alkynyl, C6-14arylC2-6alkenyl, C6-14arylC2-6alkynyl, or xe2x80x94NR19R20 (where R19 and R20 may be the same or different and are hydrogen, C1-8alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl, C6-14aryl, C6-14arylC1-6alkyl, heterocycleC1-8alkyl, C1-8alkylcarbonyl, C6-14arylsulfonyl, or R19R20 together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring), OR21 (where R21 is hydrogen, C1-8alkyl, C3-7cycloalkyl, or C6-14aryl), or SR22 (where R22 is hydrogen, C1-8alkyl, hydroxyC1-8alkyl, C3-7cycloalkyl, or C6-14aryl);
R2 is hydrogen or halogen;
R3 and R4 may be the same or different and are hydrogen, halogen, C1-8alkyl, C6-14aryl, heterocycleC6-14aryl, C1-8alkoxy, haloC1-8alkyl or xe2x80x94SR24 (where R24 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl);
Z is a substituent of formula (Ia), (Ib), or (Ic) 
wherein:
R5 is hydrogen, C1-8alkyl, haloC1-8alkyl or C1-8alkoxy;
R6 is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl or C1-8alkoxy;
R7 is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or R6 and R7 together form a ketone or alkene;
R8-R11 may be the same or different and are hydrogen, hydroxy, halogen, C2-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or any of R8 and R9 or R10 and R11 together form a ketone or alkene;
R12-R18 may be the same or different and are hydrogen, hydroxy, C1-8alkyl or hydroxyC1-8alkyl;
or a pharmaceutically acceptable derivative thereof,
provided that a compound of formula (I) cannot be 2,5-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole or 5,6-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-arabinopyranosyl)-benzimidazole-2-thione;
further provided that when Z is a substituent of formula (Ia):
a)R2, R3, and R4 cannot all be hydrogen; and
b) R1 cannot be NR19R20 where R19 and R20 together with the N atom to which they are attached form a 5 membered heterocyclic ring containing S;
further provided that when Z is a substituent of formula (Ib):
a) R1 cannot be NR19R20 where R19 and R20 together with the N atom to which they are attached form a 5 membered heterocyclic ring containing S; and
further provided that when Z is a substituent of formula (Ic):
a) and when R15-R18 are all hydrogen, then R1 cannot be hydroxy, amino or SR22 where R22 is H; and
b) R1 cannot be NR19R20 where R19 and R20 together with the N atom to which they are attached form a 5 membered heterocyclic ring containing S.
Particularly preferred R1 groups include halogen and xe2x80x94NR19R20 where R19 is hydrogen and R20 is C1-8alkyl (particularly C1-3alkyl, with isopropyl being especially preferred), C3-7cycloalkyl (cyclopropyl is especially preferred), C1-8alkylC3-7cycloalkyl or C3-7cycloalkylC1-8alkyl.
In certain particularly preferred compounds, R2 is hydrogen.
Particularly preferred R3 and R4 groups include hydrogen, halogen (chlorine is especially preferred), and C1-8alkoxy, (particularly C1-3alkoxy, with methoxy being especially preferred). In certain particularly preferred compounds, one or both of R3 and R4 are chlorine, desirably both.
In certain especially preferred compounds, R5 is hydrogen.
Particularly preferred substituents at R6-18 include hydrogen, hydroxy, C1-8alkyl (particularly C1-3alkyl, with methyl and ethyl being especially preferred) and hydroxyC1-8alkyl (particularly hydroxyC1-3alkyl, with hydroxymethyl being especially preferred).
Preferred compounds of formula (I) are compounds wherein Z is substituent of formula (Ia).
Other preferred compounds of formula (I) are compounds wherein Z is a substituent of formula (Ib).
In a further aspect of the present invention, there is provided compounds of formula (II) 
wherein:
R1 is halogen, hydroxy, azido, C1-8alkyl, C1-8alkoxy, C2-6alkenyl, C2-6alkynyl, C6-14arylC2-6alkenyl, C6-14arylC2-6alkynyl, or xe2x80x94NR19R20 (where R19 and R20 may be the same or different and are hydrogen, C18alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl, C6-14aryl, C6-14arylC1-6alkyl, heterocycleC1-8alkyl, C1-8alkylcarbonyl, C6-14arylsulfonyl, or R19R20 together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring), OR21 (where R21 is hydrogen, C1-8alkyl, C3-7cycloalkyl, or C6-14aryl), or SR22 (where R22 is hydrogen, C1-8alkyl, hydroxyC1-8alkyl, C3-7cycloalkyl, or C6-14aryl);
R2 is hydrogen or halogen;
R3 and R4 may be the same or different and are hydrogen, halogen, C1-8alkyl, C6-14aryl, heterocycleC6-14aryl, C1-8alkoxy, haloC1-8alkyl or xe2x80x94SR24 (where R24 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl);
R5 is hydrogen, C1-8alkyl, haloC1-8alkyl, C1-8alkoxy;
R6 is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy;
R7 is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or R6 and R7 together form a ketone or alkene;
R8-R11 may be the same or different and are hydrogen, hydroxy, halogen, C2-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or any of R8 and R9 or R10 and R11 together form a ketone or alkene;
or a pharmaceutically acceptable derivative thereof,
provided that a compound of formula (I) cannot be 2,5-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole or 5,6-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-arabinopyranosyl)-benzimidazole-2-thione;
further provided that when Z is a substituent of formula (Ia):
a) R2, R3, and R4 cannot all be hydrogen; and
b) R1 cannot be NR19R20 where R19 and R20 together with the N atom to which they are attached form a 5 membered heterocyclic ring containing S.
A preferred embodiment of the present invention are compounds of formula (III) 
wherein:
R1 is halogen, hydroxy, azido, C1-8alkyl, C1-8alkoxy, C2-6alkenyl, C2-6alkynyl, C6-14arylC2-6alkenyl, C6-14arylC2-6alkynyl, or xe2x80x94NR19R20 (where R19 and R20 may be the same or different and are hydrogen, C1-8alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl, C6-14aryl, C6-14arylC1-6alkyl, heterocycleC1-8alkyl, C1-8alkylcarbonyl, C6-14arylsufonyl, or R19R20 together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring), OR21 (where R21 is hydrogen, C1-8alkyl, C3-7cycloalkyl, or C6-14aryl), or SR22 (where R22 is hydrogen, C1-8alkyl, hydroxyC1-8alkyl, C3-7cycloalkyl, or C6-14aryl);
R2 is hydrogen or halogen;
R3 and R4 may be the same or different and are hydrogen, halogen, C1-8alkyl, C6-14aryl, heterocycleC6-14aryl, C1-8alkoxy, haloC1-8alkyl or xe2x80x94SR24 (where R24 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl);
R5 is hydrogen, C1-8alkyl, haloC1-8alkyl, C1-8alkoxy;
R6 is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy;
R7 is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or R6 and R7 together form a ketone or alkene;
R8 -R11 may be the same or different and are hydrogen, hydroxy, halogen, C2-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or any of R8 and R9 or R10 and R11 together form a ketone or alkene;
or a pharmaceutically acceptable derivative thereof,
provided that a compound of formula (I) cannot be 2,5-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole or 5,6-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-arabinopyranosyl)-benzimidazole-2-thione;
further provided that when Z is a substituent of formula (Ia):
a) R2, R3, and R4 cannot all be hydrogen; and
b) R1 cannot be NR19R20 where R19 and R20 together with the N atom to which they are attached form a 5 membered heterocyclic ring containing S.
Compounds of formula (I) in which Z is a substituent of formula (Ic) provide a further aspect of the invention.
Preferred compounds of formula (I), (II), and (III) are those wherein:
R1 is halogen;
R2 is hydrogen;
R3 and R4 are halogen;
R5 and R7 are hydrogen;
R6 is hydroxy or hydrogen;
R8 and R10 are hydroxy;
R9 and R11 are hydrogen;
R12 is hydrogen, C1-8alkyl, or hydroxyC1-8alkyl;
R13 is hydroxy;
R14-R18 may be the same or different and are hydrogen or hydroxy;
or a pharmaceutically acceptable derivative thereof.
A preferred compound of Formula (III) is 2-bromo-5,6-dichloro-1-xcex2-D-ribopyranosyl-1H-benzimidazole, represented by formula (XI): 
The compounds of formula (I) including compounds of formula (II) and (III) above and their pharmaceutically acceptable derivatives are hereinafter referred to as the compounds according to the invention.
The compounds according to the invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
The present invention includes within its scope each possible alpha and beta anomer of the compounds of formula (I) and their physiologically functional derivatives, substantially free of the other anomer, that is to say no more than about 5% w/w of the other anomer.
Compounds of formula (I) in the beta anomeric form are preferred.
Preferred compounds of the present invention include:
(3S,4R,5R,6S)-2-Bromo-5,6-dichloro-1-(tetrahydro4,5-dihydroxy-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole;
(xc2x1)-Trans-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexanol;
(xc2x1)-(1R*, 2S*, 3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclohexanediol;
2-bromo-5,6-dichloro-1-xcex2-D-ribopyranosyl-1H-benzimidazole;
5,6-dichloro-N-(1-methylethyl)-1-xcex2-D-ribopyranosyl-1H-benzimidazol-2-amine;
2-bromo-5,6-dichloro-4-fluoro-1-xcex2-D-ribopyranosyl-1H-benzimidazole;
2-bromo-5,6,-dichloro-1-(2,3,4-tri-O-acetyl-xcex2-D-ribopyranosyl)-1H-benzimidazole;
2-bromo-5,6-dichloro-1-xcex2-L-ribopyranosyl-1H-benzimidazole;
2-bromo-6-chloro-5-methyl-1-xcex2-D-ribopyranosyl-1H-benzimidazole; and
2-bromo-5,6,-dichloro-1-(4-deoxy-xcex2-D-erythro-pentopyranosyl)-1H-benzimidazole;
2-Bromo-5,6-dichloro-1-(beta-L-ribopyranosyl)-1H-benzimidazole;
2-Bromo-5,6-dichloro-1-(beta-L-xylopyranosyl)-1H-benzimidazole;
2-Bromo-5,6-dichloro-1-(2-deoxy-alpha-D-erythro-pentopyranosyl)-1H-benzimidazole;
or pharmaceutically acceptable derivatives thereof.
The term xe2x80x9calkylxe2x80x9d, alone or in combination with any other term, refers to a straight-chain or branch-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 1-10 and more preferably from 1-6 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like, with methyl and ethyl being preferred.
The term xe2x80x9calkenyl,xe2x80x9d alone or in combination with any other term, refers to a straight-chain or branched-chain mono-or poly-unsaturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 2-10 carbon atoms and more preferably, from 2-6 carbon atoms. References to alkenyl groups include groups which may be in the E- or Z-form or a mixture thereof and which when they contain at least three carbon atoms, may be branched. Examples of alkenyl radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutyenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z, E- and Z,Z-hexadienyl and the like.
The term xe2x80x9calkynylxe2x80x9d refers to hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to an alkyl ether radical, wherein the term xe2x80x9calkylxe2x80x9d is defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, with methoxy being preferred.
Alkenyl and alkynyl substituents may optionally contain one or more heteroatoms such as nitrogen, sulfur, or oxygen.
The term xe2x80x9caryl,xe2x80x9d alone or in combination with any other term, refers to a carbocyclic aromatic radical (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms, optionally substituted with one or more substituents selected from C1-6 alkoxy, (for example methoxy), nitro, halogen, (for example chloro), amino, carboxylate and hydroxy. Examples of aryl radicals include, but are not limited to phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
The term xe2x80x9cheterocyclexe2x80x9d and xe2x80x9cheterocyclicxe2x80x9d radical, unless otherwise defined herein, refers to a stable 3-7 membered monocyclic heterocyclic ring or 8-11 membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As used herein, the terms xe2x80x9cnitrogen and sulfur heteroatomsxe2x80x9d include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. A heterocyclyl radical may be attached at any endocyclic carbon or heteroatom which results in the creation of a stable structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles. Examples of such groups include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoqinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, oxazolyl, benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazopinyl, azepinyl, isoxozolyl, isothiazolyl, furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl, tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl, tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl, dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl.
Preferred heterocycles include imadazolyl, pyrrolyl, pyrrolinyl, piperidinyl, piperazinyl, and morpholinyl.
The term xe2x80x9chalogenxe2x80x9d refers to a radical of fluorine, chlorine, bromine or iodine.
The term xe2x80x9chaloC1-8 alkylxe2x80x9d means a C1-8alkyl group in which one or more hydrogens is replaced by halo and preferably containing one, two or three halo groups. Examples of such groups include trifluoromethyl and fluoroisopropyl.
The term xe2x80x9cpharmaceutically effective amountxe2x80x9d refers to an amount effective in treating a virus infection, for example a CMV or HBV infection, in a patient either as monotherapy or in combination with other agents. The term xe2x80x9ctreatingxe2x80x9d as used herein refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent. The term xe2x80x9cprophylactically effective amountxe2x80x9d refers to an amount effective in preventing a virus infection, for example a CMV or HBV infection, or preventing the occurrence of symptoms of such an infection, in a patient. As used herein, the term xe2x80x9cpatientxe2x80x9d refers to a mammal, including a human.
The term xe2x80x9cpharmaceutically acceptable carrier or adjuvantxe2x80x9d refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the antiviral agent.
As used herein, the compounds according to the invention are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d or xe2x80x9cpharmaceutically acceptable prodrugxe2x80x9d means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
The compounds according to the invention may be used in the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate; cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectianate, persulfate, phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-P-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium and Nxe2x80x94W+4 (wherein W is C1-4 alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts or organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+, NH4+, and NW4+ (wherein W is a C1-4alkyl group).
Pharmaceutically acceptable salts include salts of organic carboxylic acids such as ascorbic, acetic, citric, lactic, tartaric, malic, maleic, isothionic, lactobionic, p-aminobenzoic and succinic acids; organic sulphonic acids such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids and inorganic acids such as hydrochloric, sulphuric, phosphoric, sulphamic and pyrophosphoric acids.
For therapeutic use, salts of the compounds according to the invention will be pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
Preferred salts include salts formed from hydrochloric, sulfuric, acetic, succinic, citric and ascorbic acids.
Preferred esters of the compounds according to the invention are independently selected from the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C1-4alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di(C6-24)acyl glycerol.
In such esters, unless otherwise specified, any -alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
Preferred carboxylic acid esters of compounds according to the invention include the acetate, butyrate and valerate esters. L-valyl is a particularly preferred amino acid ester.
Any reference to any of the above compounds also includes a reference to a pharmaceutically acceptable salts thereof.
In a further aspect of the invention there are provided the compounds according to the invention for use in medical therapy particularly for the treatment or prophylaxis of viral infections such as herpes viral infections. Compounds according to the invention have been shown to be active against CMV infections, although early results suggest that these compounds could also be active against other herpes virus infections such as HSV-1 and -2, HHV 6, 7, and 8, VZV, EBV as well as against HBV infections.
Other viral conditions which may be treated in accordance with the invention have been discussed in the introduction hereinbefore. The compounds according to the invention are particularly suited to the treatment or prophylaxis of CMV infections and associated conditions. Examples of CMV conditions which may be treated in accordance with the invention have been discussed in the introduction hereinbefore.
According to another aspect, the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected animal, for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention. According to a particular embodiment of this aspect of the invention, the viral infection is a herpes virus infection, such as CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-or HHV-8. A further aspect of the invention includes a method for the treatment or prevention of the symptoms or effects of an HBV infection.
The compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi""s sarcoma.
The present invention further provides a method for the treatment of a clinical condition in an animal, for example, a mammal including a human which clinical condition includes those which have been discussed in the introduction hereinbefore, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention. The present invention also includes a method for the treatment or prophylaxis of any of the aforementioned infections or conditions.
In yet a further aspect, the present invention provides the use of a compound according to the invention in the manufacture of a medicament for the treatment or prophylaxis of any of the above mentioned viral infections or conditions.
The above compounds according to the invention and their pharmaceutically acceptable derivatives may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions. Combination therapies according to the present invention comprise the administration of at least one compound of the present invention and at least one other pharmaceutically active ingredient. The active ingredient(s) and pharmaceutically active agents may be administered simultaneously in either a the same or different pharmaceutical formulations or sequentially in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Preferably the combination therapy involves the administration of one compound according to the invention and one of the agents mentioned herein below.
Examples of such further therapeutic agents include agents that are effective for the treatment of viral infections or associated conditions such as (1 alpha, 2 beta, 3 alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(xe2x88x92)BHCG, SQ-34514], oxetanocin-G (3,4-bis-(hydroxymethyl)-2-oxetanosyl]guanine), acyclic nucleosides (e.g. acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir), acyclic nucleoside phosphonates (e.g. (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC), ribonucleotide reductase inhibitors such as 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone, 3xe2x80x2azido-3xe2x80x2-deoxythymidine, other 2xe2x80x2,3xe2x80x2-dideoxynucleosides such as 2xe2x80x2,3xe2x80x2-dideoxycytidine, 2xe2x80x2,3xe2x80x2-dideoxyadenosine, 2xe2x80x2,3xe2x80x2-dideoxyinosine, 2xe2x80x2,3xe2x80x2-didehydrothymidine, protease inhibitors such as indinavir, ritonavir, nelfinavir, [3S-[3R*(1R*,2S*)]]-[3[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro-3-furanyl ester (141W94), oxathiolane nucleoside analogues such as (xe2x88x92)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine) or cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3xe2x80x2-deoxy-3xe2x80x2-fluorothymidine, 5-chloro-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluorouridine, (xe2x88x92)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, ribavirin, 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), tat inhibitors such as 7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2-(H)one (Ro5-3335), 7-chloro-1,3-dihydro-5-(1H-pyrrol-2yl)-3H-1,4-benzodiazepin-2-amine (Ro24-7429), interferons such as xcex1-interferon, renal excretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine (NAC), Procysteine, xcex1-trichosanthin, phosphonoformic acid, as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD4 and genetically engineered derivatives thereof, or non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine (BI-RG-587), loviride (xcex1-APA) and delavuridine (BHAP), and phosphonoformic acid, and 1,4-dihydro-2H-3,1-benzoxazin-2-ones NNRTIs such as (xe2x88x92)-6-chloro4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266), and quinoxaline NNRTIs such as isopropyl (2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1(2H)-quinoxalinecarboxylate (HBY1293).
More preferably the combination therapy involves the administration of one of the above mentioned agents and a compound within one of the preferred or particularly preferred sub-groups within formula (I) as described above. Most preferably the combination therapy involves the joint use of one of the above named agents together with one of the compounds of formula (I) specifically named herein.
The present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least one other therapeutic agent, such as those defined hereinbefore.
In a further aspect of the present invention there is provided a method of treatment or prophylaxis of restenosis by administration of a compound according to the invention.
Restenosis is the narrowing of the blood vessels which can occur after injury to the vessel wall, for example injury caused by balloon angioplasty or other surgical techniques, and is characterized by excessive proliferation of smooth muscle cells in the walls of the blood vessel treated. Restenosis following angioplasty (RFA) occurs in patients who have been treated for coronary artery disease by balloon angioplasty. It is thought that in many patients suffering from RFA, viral infection, particularly by CMV and/or HHV-6, of the patient plays a pivotal role in the proliferation of the smooth muscle cells in the coronary vessel treated.
Restenosis can occur following a number of surgical techniques, for example, transplant surgery, vein grafting, coronary by-pass grafting and, most commonly, following angioplasty.
Angioplasty is a surgical techniques wherein atherosclerotic stenoses in the peripheral, renal and coronary vasculature are opened up by compressing and/or earing the plaque on the vessel walls, typically by means a pressurized balloon catheter. Unfortunately, in 25 to 50% of cases, particularly those involving the coronary vasculature, the treated vessel restenoses within a few months so that the operation must be repeated. Alternatives to the balloon catheter, such as pulsed lasers and rotary cutters, have been developed with a view to reducing or preventing restenosis following angioplasty, but have met with limited success. A number of drugs including anti-coagulants and vasodilators have also been tried with disappointing or equivocal results.
There is now a strong body of evidence, from work done both in vitro and in vivo, indicating that restenosis is a multifactorial process. Several cytokines and growth factors, acting in concert, stimulate the migration and proliferation of vascular smooth muscle cells (SMC) and production of extracellular matrix material, which accumulate to occlude the blood vessel. In addition growth suppressors act to inhibit the proliferation of SMC""s and production of extracellular matrix material.
The present invention further includes a process for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof which comprises:
A) Reacting a compound of formula (I) wherein R1 is hydrogen and R2, R3, and R4 are as hereinbefore defined, and R5-R18 are as hereinbefore defined, with a suitable halogenation agent such as N-bromosuccinimide (NBS); or when R1 is a suitable leaving atom or group, for example, a halo atom such as bromine or an organo (for example alkyl) sulphone, or organo (for example alkyl or aralkyl) sulphonate such as methylsulphone (MeS(O)2xe2x80x94), methylsulphonate (MeS(O)2Oxe2x80x94) or tosylate (4-MePhS(O)2Oxe2x80x94), with a nucleophile such as amines, alkoxides, mercaptides; or
B) Reacting a compound of formula (IV) 
wherein R1 is hydrogen, a halo atom, xe2x80x94NR19R20 (wherein R19 and R20 are as hereinbefore defined), and R2, R3, R4 and R5 are as hereinbefore described with a compound of formula (Va), (Vb), or (Vc) 
wherein R5-R18 are as is hereinbefore defined and L is a suitable leaving group for example, a halo (for example, fluoro, chloro or bromo), an organosulphonyloxy, an alkyl or arylthio (for example, phenylthio) or an aryl or aliphatic ester group such as benzoate or acetate, or a methoxy. Alternatively, intermediates of formula (Vb) and (Vc) where L is amino may be reacted with appropriate aromatic nitro compounds as described in WO9/07646. Thereafter or simultaneously therewith one or more of the following further steps may be additionally performed in any desired or necessary order:
(i) removing any remaining protecting group(s);
(ii) converting a compound of formula (I) or a protected form thereof into a further compound of formula (I) or protected form thereof;
(iii) converting the compound of formula (I) or a protected form thereof into a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof;
(iv) converting a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof into the compound of formula (I) or a protected form thereof;
(v) converting a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof into another pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof;
(vi) where necessary, separating the enantiomers and diastereomers of the compound of formula (I) or of a protected derivative thereof or of a pharmaceutically acceptable derivative of a compound of formula (I) using methods known to persons skilled in the art.
A. Process A may conveniently be used for the preparation of a compound of formula (I) wherein R1 is a halogen. Such compounds may conveniently be prepared by reacting a compound of formula (I) wherein R1 is hydrogen and R2-R18 are as hereinbefore defined with a halogenating agent. Halogenation may be effected in a conventional manner, for example, bromination using a brominating agent such as N-bromosuccinimide (NBS) in an aprotic solvent such as tetrahydrofuran (THF) or preferably 1,4-dioxane heated to 60-150xc2x0 C.
Compounds of formula (I) wherein R1 is xe2x80x94NR19R20 (wherein R19 and R20 are as hereinbefore defined) may conveniently be prepared from compounds of formula (I) wherein R1 is a halo atom, such as bromo or chloro atom, by reaction with an appropriate amine HNR19R20, wherein R19 and R20 are as hereinbefore defined. Typically, the reaction is effected at an elevated temperature, 70-80xc2x0 C., in an organic solvent such as ethanol or dimethylsulfoxide. Amines of formula HNR19R20 are commercially available or are readily prepared by a person skilled in the art.
Compounds of formula (I) wherein R1 is xe2x80x94OR21 (wherein R21 is as hereinbefore defined) may conveniently be prepared from compounds of formula (I) wherein R1 is a halo atom, such as bromo or chloro atom, by reaction with an appropriate alcohol of formula HOR21 (wherein R21 is as hereinbefore defined). Typically, the reaction is effected at xe2x88x9220 to 100xc2x0 C., preferably at 25xc2x0 C., in HOR21 or dimethylsulfoxide as solvent and in the presence of a strong base such as sodium hydride. Alcohols of formula HOR21 are available commercially or may be readily prepared by a person skilled in the art.
Compounds of formula (I) wherein R1 is xe2x80x94SR22 (wherein R22 is as hereinbefore defined) may conveniently be prepared from compounds of formula (I) wherein R1 is a halo atom, such as bromo or chloro atom, by reaction with an appropriate thiol of formula HSR22 (wherein R22 is as hereinbefore defined). Typically, the reaction is effected at xe2x88x9220 to 100xc2x0 C., preferably at 25xc2x0 C., in N,N-dimethylformamide or dimethylsulfoxide as solvent and in the presence of a strong base such as sodium or potassium hydride. Thiols of formula HSR2 are available commercially or may be readily prepared by a person skilled in the art.
Compounds of formula (I) in which R3 or R4 is an aryl or heterocyclic group, and R5-R18 are as hereinbefore defined, may be prepared from compounds of formula (I) in which R3 or R4 is a halo atom, such as a bromo atom, by reaction with an aryl or heterocyclic trialkyltin (IV) reagent. These reactions are typically effected in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), palladium (II) acetate, or palladium (II) chloride bis(acetonitrile) also in the presence of a solvent such as N,N-dimethylformamide and at an elevated temperature, preferably 90xc2x0 C. The desired aryl or heterocyclic trialkyltin (IV) reagent may be obtained commercially or may be readily prepared by a person skilled in the art.
The protecting groups may be removed by conventional chemical techniques well known to a skilled person.
Compounds of formula (I) wherein any of R6-R18 is a hydroxy group or R6-R11 is either a hydroxy group or a fluorine atom and R1-R5 are as hereinbefore defined may be prepared from a corresponding compound of formula (I) wherein any of R6-R18 is a protected hydroxy group or R6-R11 is a protected hydroxy group or a fluorine atom. Conventional protecting groups may be used for R6-R18. Advantageously, ester groups such as those described above in relation to the esters of compounds of formula (I) may be used. These protecting groups may be removed either by conventional chemical techniques such as sodium carbonate in water and methanol or enzymatically, for example, using pig liver esterase. Alternatively, R6-R18 may include silyl ethers such as tert-butyldiphenyl-, tert-butyldimethyl-, and triisopropylsilyl ethers which may be deprotected to give a hydroxyl group using an appropriate fluoride source, for example HF/pyridine, Bu4NF or Et4NF or a cyclic acetal or ketal such as benzylidene or isopropylidene which can be removed under acidic conditions, for example, using tosic acid and methanol.
Alternatively, the compounds of formula (I) where any of R6-R18 is a protected hydroxy group or R6-R11 is either a protected hydroxy group or a fluorine atom and R2, R3, R4 and R5 are as hereinbefore defined may be reacted with an agent or under conditions whereby the leaving group R1 is converted to the desired R1 group simultaneously with removal of the protecting groups. Examples of such agents include cyclopropylamine and other primary and secondary amines providing that these agents are sufficiently nucleophilic and are not sterically hindered.
B. Compounds of formula (I) wherein R1 is as hereinbefore defined may be prepared by reaction of a compound of formula (IV) wherein R1 is as hereinbefore defined and R2, R3, and R4 are as hereinbefore defined, with a compound of formula (V), wherein R5-R18 are as hereinbefore defined and protected when appropriate and L is as hereinbefore described. The reaction of compounds of formula (IV) with those of formula (V) may be effected using a Lewis acid such as trimethylsilyl trifluoromethanesulfonate, stannic chloride, or boron trifluoride, the former being preferred. The reaction is generally effected in an aprotic solvent and at an elevated temperature, for example, in acetonitrile at 15-30xc2x0 C. or 1,2-dichloroethane at 70-90xc2x0 C. Alternatively, the reactions of compounds of formula (IV) with those of formula (V) may be effected by applying procedures of pyrimidine nucleoside synthesis as described and referenced by Tohru Ueda in Chemistry of Nucleosides and Nucleotides, vol. 1 (Leroy B. Townsend, ed.) pp. 1-112, Plenum Press, New York, 1988 or purine nucleoside synthesis as described and referenced by Prem C. Srivastva, Roland K. Robins and Rich B. Meyer, Jr., ibid, pp. 113-281 or pyranose nucleoside synthesis as described and referenced by P. Herdewiijn, A. Van Aerschot, J. Balzarini and E. De Clerq in Nucleosides and Nucleotides, Volume 10, 1991, pp. 119-127, and U.S. Pat. No. 5,399,580, incorporated herein by reference hereto.
The compound of formula (IV) is advantageously trimethylsilylated at the N1-position in the above procedures to improve solubility; for example, by treatment with trimethylsilylchloride, hexamethyl disilazane or, most preferably, N,O-bis(trimethylsilyl)acetamide (BSA). The silylation can be effected in a solvent, preferably 1,2-dichloroethane or acetonitrile, preferably at 70-80xc2x0 C. After completion of the silylation reaction, a Lewis acid may be added, followed by the addition of the compound of formula (V).
Compounds of formula (Va) may be purchased, for example, from Aldrich (Milwaukee, Ill.) or Pfanstiehl (Waukegan, Ill.) or may be prepared by literature methods well known to persons skilled in the art, for example J. Barbat et at., Carbohydrate Research, 116 (1983), pp. 312-316; M. Fuertes et al., J. Org. Chem., 40 (1975), pp. 2372-2377; L. Lerner et al., J. Med. Chem., 30 (1987), pp. 1521-1525.
Compounds of formula (Va) in which R5 is as hereinbefore defined and only one of R6-R11 is an unprotected hydroxyl and L is methoxy may undergo deoxygenation via a phenyl thiocarbonate prepared by reaction of the previous free hydroxyl with a chlorothionoformate such as phenylchlorothioformate. The intermediate thionocarbonate is removed via a reductant, such as tributyltin huydride. This reaction is typically effected in the presence of a radical initiator, 2,2xe2x80x2-azobisisobutyronitrile, for example, and in the presence of an aromatic solvent, toluene for example. This intermediate can then eventually be converted to a compound of formula (Va) in which hydroxyls are protected as esters, acetyl esters for example, by reaction with an acid, acetic acid for example, and an acylating agent, acetic anhydride for example. This reaction is typically effected in the acylating agent as solvent at 0-100xc2x0 C. alternatively, deoxygenation may be effected. for example, as described by P. Collins and R. Ferrier in Monosaccharides (1995), John Wiley and Sons, New York, p. 213, and references therein.
Fluorinated compounds of formula (Va) may be prepared by methods known to one skilled in the art, for example, by reaction of an unprotected hydroxyl group of a compound of formula (Va) with a fluorinating agent, diethylaminosulfur trifluoride for example. This reaction is typically effected in an aprotic solvent, such as chloroform or toluene, and at an elevated temperature, advantageously 75xc2x0 C. Fluorinated and other halogenated deoxy sugars of formula (Va) may also be prepared in analogous fashion as described for like and different carbohydrates by P. Collins and R. Ferrier in Monosaccharides (1995), John Wiley and Sons, New York, pp. 248-262 and references therein.
Compounds of formula (Va) in which R5 is as hereinbefore defined and only one of R6-R11 is an unprotected hydroxy may be oxidized to a ketone by methods known to persons skilled in the art, for example methods described or referenced by R. C. Petter et al. in Tetrahedron Letters, 30 (1989), pp. 659-662, S. Czernecki et al. in Tetrahedron Letters, 26 (1985), pp. 1699-1702, or M. Hudlicky in Oxidations in Organic Chemistry ACS Monograph 186 (1990), American Chemical Society, Washington D.C. Such ketone compounds may be treated with appropriate Grignard reagents or alkyl metal reagents and carbon nucleophiles to effect alkylation to give a new compound of formula (Va), for example, as described by P. Collins and R. Ferrier in Monosaccharides (1995), John Wiley and Sons, New York, p. 3092 and references therein. Additionally Wittig reagents may be employed to prepare olefins of formula (Va), for example, as described by P. Collins and R. Ferrier, ibid, p. 263 and references therein or as described by R. C. Petter et al. in Tetrahedron Letters, 90 (1989), pp. 659-662. Hydroboration-oxidation of olefins of formula (Va) using procedures described by H. Redlich et al. in Synthesis, (1992), pp. 1112-1118 or as described by Acton et al. in the Journal of Medicinal Chemistry, 22 (1972), pp. 518-526, leads to hydroxyl methyl derivatives of formula (Va). Additionally, hydride reagents may be used to effect inversion of hydroxyl stereochemistry of R6-R11 from such a described ketone by methods known to persons skilled in the art and using commonly accepted appropriate practices of carbonyl reduction as those described by M. Hudlicky in Reductions in Organic Chemistry ACS Monograph 188 (1996), American Chemical Society, Washington, D.C., pp. 149-190.
Compounds of formula (Vb) and (Vc) may be made by methods known to persons skilled in the art.
Compounds of formula (IV), wherein R1 is hydrogen or a halo atom, most preferably chloro or bromo, and R2, R3, and R4 are as hereinbefore defined, may be prepared in accordance with the methods described in PCT specification WO92/07867 incorporated herein by reference. Alternatively, compounds of formula (IV), wherein R1 is hydrogen or a halo atom, most preferably chloro or bromo, and R2, R3, and R4 are as hereinbefore defined, may be prepared in accordance with the methods described by Leroy Townsend, et al. J. Med. Chem., Vol. 38, 1995, pg. 4098.
Alternatively, compounds of formula (IV) wherein R1 is xe2x80x94NR19R20 wherein R19 and R20 are as hereinbefore defined, may be prepared by reacting a compound of formula (VI) 
wherein R2, R3, and R4 are as hereinbefore defined, with an agent capable of cyclizing the diamine into a benzimidazole. Typically, compounds of formula (VI) may be reacted with an isothiocyanate of formula (VII)
Sxe2x95x90Cxe2x95x90NR19xe2x80x83xe2x80x83(VII)
wherein R19 is as hereinbefore defined. The reaction may be carried out in the presence of an agent to promote cyclization such as methyl iodide or a carbodiimide such as dicyclohexyl carbodiimide or, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate in the presence of an aprotic aromatic solvent such as toluene and most preferably pyridine and at an elevated temperature, preferably 75-150xc2x0 C.
Compounds of formula (VII) may be prepared by methods well known skilled person or readily available in the chemical literature or obtained comercially.
Compounds of formula (IV) wherein R1 is hydrogen may be obtained commercially or alternatively may be prepared by reacting a compound of formula (VI) wherein R2, R3, and R4 are as hereinbefore defined with formamidine or most preferably formic acid at ambient temperature to 100xc2x0 C., advantageously 80xc2x0 C.
Compounds of formula (VI) may be obtained commercially or may be prepared by methods known to persons skilled in the art or readily available in the chemical literature.
Alternatively, compounds of formula (VI) may be conveniently prepared from compounds of formula (VIII) 
wherein R2, R3, and R4 are as hereinbefore defined, in the presence of a reducing agent, reduced iron for example, and in the presence of an acid, most preferably hydrochloric acid, and in the presence of a solvent such as ethyl alcohol and in the temperature range of 50-78xc2x0 C. (B. Fox and T. L. Threlfall, Org. Syn. Coll. Vol. 5, 1973, p. 346). Alternatively, such ortho phenylenediamines may be prepared in the presence of a reducing agent such as Raney nickel also in the presence of hydrogen. This reaction is also run in the presence of a solvent, ethyl alcohol for example, at ambient temperature (K. Dimroth, et al, Org. Syn. Coll. Vol. 5, 1973, p.1130). Alternatively, such ortho phenylenediamines may be prepared in the presence of a reducing agent such as sodium hydrosulfite. Typically this reaction is effected in the presence of a polar, protic solvent, preferably a mixture of water and ethanol, and at an elevated temperature, preferably reflux.
Compounds of formula (VIII) may be prepared by methods well known to a skilled person or are readily available commercially. Alternatively, compounds of formula (VIII), where R2 is a halogen atom such as fluorine, chlorine or bromine atom, and R3 and R4 are as hereinbefore defined, may be prepared from compounds of formula (VIII) wherein R2 is hydrogen by reaction with an appropriate halogenating agent such as 1-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), N-chlorosuccinimide or N-bromosuccinimide, in the presence of an aprotic solvent such as acetonitrile or N,N-dimethylformamide and at an elevated temperature from 50-100xc2x0 C.
Alternatively, compounds of formula (VII) wherein R4 is xe2x80x94SR24 (wherein R24 is as hereinbefore defined) may be prepared from compounds of formula (VIII) wherein R4 is a halo atom and R2 and R3 are as hereinbefore defined by reaction with HSR24. This reaction is typically effected in the presence of a strong base such as sodium or potassium hydride and in the presence of a solvent such as dimethylsulfoxide, most preferably N,N-dimethylformamide at ambient temperatures.
Alternatively, compounds of formula (VIII) may advantageously be prepared from compounds of formula (IX), 
wherein R25 is hydrogen, R26 is a protecting group such as an amide, trifluoroacetamide for example, and R2, R3, and R4 are as hereinbefore defined, by reaction with a nitrating agent such as nitric acid. This reaction is effected in a solvent such as sulfuric acid at temperatures of xe2x88x9220 to 25xc2x0 C., most preferably at 0xc2x0 C. The protecting group, R26, may be conveniently removed at the end of the reaction sequence with either acid, 2 normal sulfuric acid for example, or base, sodium carbonate in methanol and water for example, at temperatures of 25-100xc2x0 C.
Compounds of formula (IX) wherein R25 is hydrogen and R26 is a protecting group such as an amide, trifluoroacetamide for example, and R2, R3 and R4 are as hereinbefore defined, may be prepared from compounds of formula (IX) wherein R25 and R26 are hydrogen and R2, R3 and R4 are as hereinbefore defined by reaction with an appropriate acylating agent such as trifluoroacetic anhydride. These reactions are effected in the presence of an aprotic solvent such as acetontrile, most preferably 1,4-dioxane, from xe2x88x9210 to 40xc2x0 C., advantageously at 0xc2x0 C.
Alternatively, compounds of formula (VIII) in which R2, R3 and R4 are as hereinbefore defined can be prepared from compounds of formula (X) 
wherein R27 is a halo atom, fluoro or chloro atom for example, by reaction with ammonia. These reactions are typically effected in the presence of a solvent such as ethyl alcohol or 1,4-dioxane and at elevated temperatures, advantageously 100xc2x0 C.
Compounds of formula (IX) in which R25 and R26 are hydrogen and R2, R3 and R4 are as hereinbefore defined may be prepared by methods well known to a skilled person or readily available in the chemical literature or obtained commercially.
Compounds of formula (X) may be obtained commercially or may be readily prepared by a person skilled in the art.
Compounds of formula (I) wherein Z is a substituent of formula (Ib) may be made according to Scheme I or by any method known to persons skilled in the art. 
Compounds of formula (I) wherein Z is a substituent of formula (Vb) or (Vc) may be made according to U.S. Pat. Nos. 5,399,580, 5,534,535 and WO96/07646, incorporated herein by reference hereto.
The compounds according to the invention, also referred to herein as the active ingredient, may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the infection and the chosen active ingredient.
In general a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 100 mg per kilogram body weight per day and most preferably in the range 0.5 to 30 mg per kilogram body weight per day and particularly in the range 1.0 to 20 mg per kilogram body weight per day. Unless otherwise indicated, all weights of active ingredient are calculated as the parent compound of formula (I); for salts or esters thereof, the weights would be increased proportionally. The desired dose may be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1000 mg or 50 to 500 mg, preferably 20 to 500 mg, and most preferably 100 to 400 mg of active ingredient per unit dosage form.
While it is possible for the active ingredient to be administered alone it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
The present invention further includes a pharmaceutical formulation as hereinbefore defined wherein a compound of formula (I) or a pharmaceutically acceptable derivative thereof and at least one further therapeutic agent are presented separately from one another as a kit of parts.
Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is about 1% to 25%, preferably about 3% to 15%. As one particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3 (6), 318 (1986).
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.
Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. xe2x80x9cActive ingredientxe2x80x9d denotes a compound according to the invention or multiples thereof or a physiologically functional derivative of any of the aforementioned compounds.
General Procedures
General Procedure I: Reduction of Substituted Nitroanilines to Substituted Phenylenediamines
The appropriate substituted nitroaniline (115-145 mmol), ethanol and Raney nickel (7-8 g wet) (Aldrich, Milwaukee) were combined in a stirred Parr reactor which was pressurized with hydrogen (between 200 and 300 psig). The mixture was allowed to stir at rt overnight, after which time the reactor was depressurized and the mixture was filtered through Celite and the solvents were removed in vacuo to yield a solid appropriate for ring closure to a benzimidazole as describe in General Procedure II.
General Procedure II: Synthesis of Substituted Benzimidazole Bases from Substituted Phenylenediamines
To the appropriate substituted phenylenediamine dissolved in enough aqueous 4N HCl to make a 100 mM solution was added 1.25-1.3 equivalents/phenylenediamine of aqueous 88% formic acid. The resulting solution was refluxed between 3 and 18 h followed by cooling to rt and neutralization to pH 7, as determined by indicator paper, with either aqueous sodium hydroxide or ammonium hydroxide. The resulting solid was filtered into a sintered glass funnel, washed with copious amounts of water, air dried then vacuum dried at 50xc2x0 C. for 24 h or longer. Benzimidazoles thus prepared were suitable for coupling to peracetylated ribopyranose.
General Procedure III: Coupling of 2-bromo-1H-benzimidazoles or 2-unsubstituted Benzimidazoles with Peracetylated Pyranoses
The appropriate benzimidazole was magnetically stirred under a nitrogen atmosphere in an oven dried round bottomed flask equipped with a stir bar and reflux condenser in anhydrous 1,2-dichloroethane (Aldrich, Milwaukee) or acetonitrile (Aldrich, Milwaukee). To the stirring suspension was added 1 equivalent/benzimidazole of N,O-bis(trimethylsilyl)acetamide and the resulting mixture was refluxed for 1 to 3 h. The resulting solution was allowed to cool to rt. To this solution was added 1 equivalent/benzimidazole of a peracetylated pyranose followed by 0.50 to 1.1 equivalent/benzimidazole of trimethylsilyl trifluoromethanesulfonate (Aldrich, Milwaukee) or 1.4 to 5 equivalents stannic chloride/benzimidazole from a 1 M solution in dichloromethane (Aldrich, Milwaukee). The new mixture was then heated in an oil bath ca. 85xc2x0 C. between 0.5 to 24 h as determined by conversion of starting material to product(s) by TLC. Reactions were quenched by pouring the reaction into ca. 7% aqueous sodium bicarbonate and extraction with dichloromethane or ethyl acetate until product was not apparent in the aqueous layer. The organic layer was dried over magnesium sulfate, filtered and solvent removed using a rotrary evaporator. The products were further purified by silica gel column chromatography.
General Procedure IV: Bromination of N-1 Benzimidazole Pyranosides Unsubstituted at C-2
Typically a benzimidazole pyranoside unsubstituted at C-2 was dissolved in enough THF to make a solution between 10 and 30 mM. The solution was refluxed in a rb with an attached reflux condenser and magnetic stirring under a nitrogen atmosphere by an oil bath at ca. 85xc2x0 C. 2 equivalents/benzimidazole pyranoside of N-bromosuccinimide (NBS, Aldrich, Milwaukee) was added every 15 min to the refluxing solution until bromination of starting material was complete as evidenced by TLC. The reaction was quenched by pouring into cold 7% aqueous sodium bicarbonate and extraction with dichloromethane until product was not apparent in the aqueous layer. The dichloromethane layer was further washed with 4 equivalent volumes of aqueous sodium bicarbonate then 1 volume of water. The organic layer was dried over magnesium sulfate, filtered and solvent removed using a rotrary evaporator. The products were further purified by silica gel column chromatography.
General Procedure V: Deprotection of N-1 2-Bromobenzimidazole Acetylated Pyranosides by 1M Aqueous Lithium Hydroxide
The appropriate N-1 2-bromobenzimidazole acetylated pyranoside was dissolved in enough dioxane to make a solution between 100 and 200 mM. To the solution was added 1.3 equivalents/acetate to be deblocked of aqueous 1M LiOH. The mixture was allowed to stir between 0.25 and 1 h followed by the addition of enough pH 7 phosphate buffer (VWR, West Chester) to make the resulting solution neutral as shown by pH indicator strips. The mixture was extracted with ethyl acetate until product was not present in the aqueous layer as indicated by TLC. The ethyl acetate layer was washed with 1 equal volume of water, then dried over magnesium sulfate, filtered and solvent removed using a rotary evaporator. Products were further purified by trituration of the solid in dichloromethane and collection of the solid by vacuum filtration onto a sintered glass funnel.
General Procedure VI: Deprotection of N-1 2-Bromobenzimidazole Acetylated Pyranosides by Sodium Carbonate in 4:4:1 Ethanol:Methanol:Water Mixture
Every 100 mg of the appropriate N-1 2-bromobenzimidazole acetylated pyranoside was dissolved in 4 ml of methanol followed by the addition of an equivalent volume of ethanol. 2.2 equivalents of sodium carbonate/acetate to be deprotected was added dropwise to the alcoholic solution in an aqueous solution one-fourth the volume of methanol previously used. The suspension was allowed to stir between 2 and 24 h. When TLC indicated that deprotection of acetates from the pyranoside was complete, the suspension was filtered, diluted with water and the solution made neutral with acetic acid as demonstrated by pH indicator paper. The mixture was partitioned between ethyl acetate and water. The aqueous layer was repeatedly extracted with ethyl acetate until all product was in the organic layer. The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. Products were further purified by trituration of the resulting solid in dichloromethane and collection of the new solid by vacuum filtration onto a sintered glass funnel.